title: Estrogen alters the splicing of type 1 corticotropin-releasing hormone receptor in breast cancer cells.
abstract: Hormonal stress response is associated with the pathogenesis of disease, including cancer. The role of the stress hormone CRH (corticotropin-releasing hormone) in breast cancer is complex, and its abundance and biological activity may be modulated by estrogen. In the estrogen receptor-positive (ER+) malignant mammary epithelial cell line MCF7, CRH activated numerous kinases and downstream effectors, at least some of which were mediated by the CRH receptor type 1 (CRH-R1). CRH also increased the transcription of many genes that encode effectors, transcriptional targets, or regulators associated with estrogen signaling. Estrogen increased the abundance of the mRNA encoding CRH-R2 and an alternative splice variant encoding CRH-R1 in which exon 12 was deleted [CRH-R1(Δ12)]. Estrogen inhibited the expression SRSF6, which encodes serine/arginine-rich splicing factor 55 (SRp55). An increase in CRH-R1(Δ12), in response to either estrogen or SRp55 knockdown, dampened the cellular response to CRH and prevented its inhibitory effects on cell invasion. SRp55 knockdown also induced additional splicing events within exons 9 to 12 of CRH-R1, whereas overexpression of SRp55 prevented estrogen-induced generation of CRH-R1(Δ12). ER+ breast tumors had increased CRH-R2 and CRH-R1(Δ12) mRNA abundance, which was associated with decreased abundance of the mRNA encoding SRp55, compared with the amounts in ER- tumors, suggesting that estrogen contributes to the pathophysiology of ER+ breast cancer by altering CRH receptor diversity and disrupting CRH-mediated signaling.
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Suchita
authors.initials: S
authors.lastname: Lal
authors.forename: Anna
authors.initials: A
authors.lastname: Allan
authors.forename: Danijela
authors.initials: D
authors.lastname: Markovic
authors.forename: Rosemary
authors.initials: R
authors.lastname: Walker
authors.forename: James
authors.initials: J
authors.lastname: Macartney
authors.forename: Nick
authors.initials: N
authors.lastname: Europe-Finner
authors.forename: Alison
authors.initials: A
authors.lastname: Tyson-Capper
authors.forename: Dimitris K
authors.initials: DK
authors.lastname: Grammatopoulos
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D004967:Estrogens; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D011960:Receptors, Estrogen; C489470:SRSF6 protein, human; D000068103:Serine-Arginine Splicing Factors; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3